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NIH Public Access Author Manuscript Bioorg Med Chem NIH Public Access Author Manuscript Bioorg Med Chem. Author manuscript; available in PMC 2013 July 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Bioorg Med Chem. 2012 July 1; 20(13): 4020–4031. doi:10.1016/j.bmc.2012.05.011. Antitumor agents 290. † Design, synthesis, and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens Qian Shia,c,*, Koji Wadaa, Emika Ohkoshia, Li Lina, Rong Huanga, Susan L. Morris- Natschkea, Masuo Gotob, and Kuo-Hsiung Leea,d,* aNatural Products Research Laboratories, UNC Eshelmen School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA bCell and Developmental Biology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7090, USA cAndroScience Corporation, 11175 Flintkote Ave., Suite F, San Diego, CA 92121, USA dChinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan Abstract In our continuing study of curcumin analogs as potential anti-prostate cancer drug candidates, 15 new curcumin analogs were designed, synthesized and evaluated for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Twelve analogs (5-12, 15, 16, 19, and 20) are conjugates of curcumin (1) or methyl curcumin (2) with a flutamide- or bicalutamide-like moiety. Two compounds (22 and 23) are C4-mono- and difluoro-substituted analogs of dimethyl curcumin (DMC, 21). Among the newly synthesized conjugates compound 15, a conjugate of 2 with a partial bicalutamide moiety, was more potent than bicalutamide alone and essentially equipotent with 1 and 2 against both prostate tumor cell lines with IC50 values of 41.8 μM (for LNCaP) and 39.1 μM (for PC-3). A cell morphology study revealed that the cytotoxicity of curcumin analogs or curcumin-antiandrogen conjugates detected from both prostate cancer cell lines might be due to the suppression of pseudopodia formation. A molecular intrinsic fluorescence experiment showed that 1 accumulated mainly in the nuclei, while conjugate 6 was distributed in the cytosol. At the tested conditions, antiandrogens suppressed pseudopodia formation in PC-3 cells, but not in LNCaP cells. The evidence suggests that distinguishable target proteins are involved, resulting in the different outcomes toward pseudopodia suppression. Keywords Synthesis; Curcumin analogs; Conjugates; Cytotoxicity; Anti-prostate cancer; Morphology †Antitumor agents 290. For paper 289, see ref 1. © 2012 Elsevier Ltd. All rights reserved. *To whom correspondence should be addressed. Phone: Qian Shi: (919)-843-6325, Fax: (919)-966-3893, [email protected]; Kuo- Hsiung Lee: (919)-962-0066, Fax: (919)-966-3893, [email protected]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Shi et al. Page 2 1. Introduction Statistically, prostate cancer is still ranked as the most common cancer in American males NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript (28%) and was the second leading cause of cancer-related death among men in the United States (11%) in 2010.2 Constitutive activation of the androgen receptor (AR) by high levels of androgens is presumed to be responsible for the progression of prostate cancer. Most presently available chemotherapeutic agents are antiandrogens, including steroidal anti- androgens and nonsteroidal antiandrogens. The steroidal antiandrogens, such as cyproterone acetate, possess partial agonistic activity to the AR and inter-activity with other hormonal systems, which can induce many complications.3-5 The nonsteroidal antiandrogens, such as flutamide and bicalutamide, have fewer side effects and were thought to be pure AR antagonists. However, antiandrogen withdrawal syndrome has been discovered in patients treated with nonsteroidal antiandrogens for several months.6-7 One proposed mechanism for this syndrome is a mutation of the AR caused by the long-term use of these nonsteroidal antiandrogens, so that the nonsteroidal antiandrogens exhibit agonistic activity to the mutant AR.8 Flutamide and bicalutamide (a racemic mixture) (Figure 1) are two well- known nonsteroidal antiandrogens, widely used for the clinical treatment of prostate cancer.9-10 However, induction of antiandrogen-withdrawal syndrome in patients has been a considerable problem. Combination usage with a gonadotropin-releasing hormone agonist, such as goserelin acetate or leuprolide acetate, is currently recommended and used in the clinic to minimize antiandrogen withdrawal syndrome.11 To date, none of the effective clinically available antiandrogens is able to kill prostate cancer cells. Curcumin (1) (Figure 1), a major yellow pigment of Curcuma longa, has been, reported to have to have anti-prostate cancer activity in vitro and in vivo.12-14 Although the mechanism of action is still unknown, it has been associated with multiple proteins/signaling pathways, such as NF-kB,15 STATs,16 AP-1,17 MAPK,18 and Akt,19 etc. More recently, Ras has been reported to be a potential target protein related to the anticancer activity.20 However, the metabolic instability of 1 leads to its poor bioavailability, which, in part, prevents 1 from being used as an efficient therapeutic drug.21-23 Other reports have identified curcumin analogs that were cytotoxic against androgen-dependent LNCaP cells and androgen- independent PC-3 cells.24-27 Some analogs demonstrated potent anti-AR activity in LNCaP cells and PC-3 cells transfected with wild type AR, and were even more potent than hydroxyflutamide, the active metabolite of flutamide,28-29 although again, the exact mechanism of action remains unclear. It is also known that the conjugation of antitumor drugs with other components such as antioxidants or other antitumor agents has provided some advantages in improving the antitumor efficacy and selectivity, while decreasing the systematic toxicity.30-32 In our search for new anti-prostate cancer drugs with increased potency and minimized adverse antiandrogen effects, we considered conjugation of curcumin or its analogs with clinically used antiandrogens, such as flutamide and bicalutamide, to be a possible approach to develop new anti-prostate cancer leads, in addition to the conventional structural modification of the curcumin molecule alone. Although 1 has been extensively studies recently in combinations with different cancer therapeutic agents to treat cancers through synergistic activity,33-34 the conjugation of 1 (or its analog) with a cancer therapeutic agent has not been explored. Unlike the principle of drug combination, the biological activity of a conjugate basically results from a single molecule in which two or more active components are tethered through covalent chemical bonds. The mechanism of action of the conjugate, therefore, could be different from that of the combination forms. Ideally, the advancement of the conjugation approach lies in “one molecule double or multiple functions”.35 This field merits exploration, and in this manner, we hope to develop new drug candidates potentially inhibiting proliferation of prostate cancer cells and mitigating the side effects of existing Bioorg Med Chem. Author manuscript; available in PMC 2013 July 01. Shi et al. Page 3 antiandrogens. Structurally, flutamide and bicalutamide share a N-(4-substituted-3- (trifluoromethyl)phenyl)acetamido moiety, which may be an essential pharmacophore for NIH-PA Author Manuscript NIH-PA Author Manuscripttheir NIH-PA Author Manuscript anti-prostate cancer activity. New conjugates in which curcumin (1) or methyl curcumin (2) were coupled with a flutamide molecule (or N-arylmethacrylamide moiety of bicalutamide) through various linkages were designed and synthesized (Figure 2). The in vitro anti-prostate cancer activity of the newly synthesized entities was examined and will be used to guide further optimization of new conjugates. It is also known that an enol-ketone linkage in 1 (and its analogs) is an important structural feature for its biological activities.25 In order to further confirm this interesting structure-activity phenomenon and the effectiveness of both enol-ketone/diketone isomers on prostate cancer, we designed and synthesized compounds 22 and 23, which contain fluorine as an isostere of hydrogen at the C4 position.36 With the mono-fluoro substitution, we expect that 22 will be stabilized as only the enol-ketone isomer, while the di-fluoro substituted 23 should retain the diketone form without tautomerization to an enol-ketone isomer. We also determined the subcellular distribution of 1 and its conjugate 6 in PC-3 cells by capturing their intrinsic fluorescence, and observed clear dissimilarity. From these preliminary results, we hope to gain information not only on new SAR but also regarding promising new anti-prostate cancer leads and mechanism of action. 2. Results and Discussion 2.1. Chemistry The starting material 2 was prepared according to a reported synthetic method.37 As illustrated in Scheme 1, the conjugation of 1 or 2 with flutamide-related
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